Heart failure (HF) is a global problem with an estimated prevalence of 38 million patients worldwide, including 6 million in the United States and more than 550,000 new patients diagnosed with the condition in the US each year. HF is the most common diagnosis in patients aged 65 years or older admitted to hospital and it is one of the most significant causes of morbidity and mortality in developed countries.
Heart failure is a clinical syndrome characterized by the failure of the heart to pump sufficient blood to meet the body's systemic demands. The heart contracts and relaxes with each heartbeat—these phases are referred to as systole (the contraction phase) and diastole (the relaxation phase). Systolic heart failure (SHF) is characterized by low ejection fraction. In patients with diastolic heart failure (DHF), contraction may be normal but relaxation of the heart may be impaired. This impairment is generally caused by a stiffening of the ventricles. Such impairment is referred to as diastolic dysfunction and if severe enough to cause pulmonary congestion (increased pressure and fluid in the blood vessels of the lungs), diastolic heart failure. DHF patients differ from those patients with SHF, in that DHF patients may have a “normal” ejection fraction. However, because the ventricle doesn't relax normally, the pressure within the ventricle increases and the blood filling the ventricle exceeds what is “normal”. People with certain types of cardiomyopathy may also have diastolic dysfunction.
Left ventricular hypertrophy (LVH) refers to a thickening of the left ventricle as a result of increased left ventricular load. LVH can be a significant marker for cardiovascular disorders and most common complications include arrhythmias, heart failure, ischemic heart disease, and sudden death. Although LVH increases naturally with age, it is more common in people who have high blood pressure or have other heart problems. Because LVH usually develops in response to hypertension, current treatment and prevention mainly includes managing hypertension. Typical diagnosis involves the use of echocardiograms (ECHO) and electrocardiograms (ECG).
Myocardial infarction (MI) is a leading cause for heart failure. The mechanism of an MI often involves the rupture of an atherosclerotic plaque leading to complete blockage of a coronary artery which resulted in the death or damage of heart muscle cells because the heart muscle cells do not receive enough oxygen. Diabetes mellitus (type 1 or 2), high blood pressure, dyslipidemia/high levels of blood cholesterol, particularly high low-density lipoprotein, low high-density lipoprotein, high triglycerides, and obesity have all been linked to myocardial infarction (Jay N. Cohn, et al., Journal of the American College of Cardiology, 35(3), 569-82, 2000). Long-term outcome after MI can be largely be defined in terms of its impact on the size and shape of the left ventricle (i.e., LV remodeling). Three major mechanisms contribute to LV remodeling: i) early infarct expansion, ii) subsequent infarct extension into adjacent non infarcted myocardium, and iii) late hypertrophy in the remote LV (Id). As the heart remodels, it not only gets bigger, but the cardiac walls get thinner and the pumping capacity of the heart declines. Cardiac remodeling is generally accepted as a determinant of survival after recovery from MI. Although the importance of remodeling as a pathogenic mechanism is incompletely understood, cardiac remodeling is thought to be an important aspect of disease progression in HF, regardless of cause (Id). Left ventricular remodeling is the process by which ventricular size, shape, and function are regulated by mechanical, neuro-hormonal, and genetic factors. Remodeling may be physiological and adaptive during normal growth or pathological due to MI, cardiomyopathy, hypertension, or valvular heart disease (French and Kramer, Drug Discov. Today Dis Mech., 4(3): 185-196, 2007).
It was recently reported that glucagon receptor signaling in cardiomyocytes modulates outcomes in non-diabetic mice with experimental myocardial infarction (Ali, et al., Molecular Metabolism, 4:132-143, 2015). Specifically, exogenous glucagon administration directly impaired recovery of ventricular pressure in ischemic mouse hearts ex vivo, and increased mortality from myocardial infarction after LAD coronary artery ligation in mice in a p38 MAPK-dependent manner. In contrast, cardiomyocyte specific reduction of glucagon action in adult GCGRCM-/- mice (mice having GCGR inactivated) significantly improved survival, and reduced hypertrophy and infarct size following myocardial infarction (Id.) The authors conclude that the cardiovascular consequences of manipulating glucagon action remain poorly understood and emphasize the need to acquire a further understanding of such consequences (Id.)
Current drug treatments available for management of heart failure, and other cardiovascular disorders, include vasodilators to reduce the blood pressure and ease the workload of the heart, diuretics to reduce fluid overload, inhibitors and blocking agents of the body's neuro-hormonal responses (e.g., angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic blocking agents), and other medicaments. Such medications, while effective for a short time, often cannot be used for extended periods because of side effects. Various surgical procedures such as heart transplantation have also been proposed for patients who suffer from severe, refractory heart failure. Alternatively, an implantable medical device such as ventricular assist devices (VADs) may be implanted in the chest to increase the pumping action of the heart, or an intra-aortic balloon pump (IABP) may be used for maintaining heart function for short periods of time, but typically no longer than one month. While each of these approaches have proven to be at least partly beneficial to patients, they each have shortcomings which limit their overall effectiveness. For example, drug therapies often involve unwanted side effects and complex therapy regimens which contribute to poor patient compliance. And both drug therapy and surgical approaches are very costly, adding to the health care costs associated with heart failure. Despite the ongoing research and development of treatments for heart failure, there is still a tremendous need for improved and alternative treatments.